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Eph

Members of the Eph receptor tyrosine kinase (RTK) family function as receptors and ligands for membrane-anchored ephrins. The Eph/ephrin system thus has the capacity to transduce signals into both the Eph- and ephrin-expressing cells. The Eph ectodomain is comprised of an N-terminal ephrin-binding domain, a cysteine-rich EGF-like domain and two membrane-proximal fibronectin type-III motifs. A single-pass hydrophobic transmembrane domain anchors Eph receptors in the plasma membrane and is contiguous with a cytoplasmic tail containing a regulatory juxtamembrane domain, a protein tyrosine kinase domain, a sterile a motif and a PDZ domain-binding C-terminal tail. Two Eph receptor subclasses (A and B) are defined on the basis of binding preferences for ephrin ligands. EphA receptors preferentially bind glycosylphosphatidylinositol (GPI)-anchored A-subclass ephrins, and EphB receptors preferentially bind transmembrane B-subclass ephrins. However, some inter-subclass binding events are significant, such as EphA4/ephrinB2 and ephrinB3, and EphB2/ephrinA5.

EphB2 clustering is initiated by dimeric ephrinB2 binding to a high affinity site to form a 2:2 complex. This tetrameric complex is recruited to ring-like structures via a low affinity interface whereby one ephrin binds two Eph receptors. EphB2 clustering relieves catalytic autoinhibition through transphosphorylation of two tyrosine residues in the cytoplasmic juxtamembrane sequence, simultaneously creating docking sites for SH2 domain-containing proteins. Further Eph receptor autophosphorylation, and phosphorylation of recruited substrates, on tyrosine residues initiates forward signaling. The recruitment of proteins containing PDZ domains to Eph receptor C-termini is also believed to play a role in the transduction of forward signals, but the regulation and in vivo significance of PDZ interactions remain poorly characterized. The activation of signal transduction into the ephrin-expressing cell is known as reverse signaling. While A-subclass ephrins can mediate reverse signaling, the mechanism is unknown. B-subclass ephrins share a conserved cytoplasmic tail and mediate reverse signaling via Src family kinase-dependent tyrosyl phosphorylation and the recruitment of adaptors such as Grb4. The C-termini of B-subclass ephrins also recruit proteins containing PDZ domains.

Eph/ephrin engagement at the cell surface signals bidirectionally to regulators of the actin cytoskeleton and cell-substrate adhesions to couple cell-cell contact with context-specific changes in motility and adhesion. While the more common outcome of Eph/ephrin engagement is unilateral or mutual cell de-adhesion or repulsion (e.g. restriction of cell intermingling at the interface of EphA4/ephrinB expression domains in adjacent rhombomeres), an adhesive response is generated under specific circumstances (e.g. in epithelial fusion during septation of the urinary and alimentary tracts mediated by EphB2/ephrinB2). Mechanisms which determine the cellular response to Eph/ephrin activation are complex and include ephrin ectodomain cleavage, endocytosis of Eph/ephrin complexes, extent of Eph/ephrin clustering, expression of truncated Eph receptor, Eph/ephrin engagement in cis, differential activation of signaling pathways and cell type-specific expression of signal transduction effectors. Crosstalk with other receptors and bidirectional signaling initiated by contact between cells which both coexpress Eph and ephrins may also play a role.

Although Eph receptors contribute to the regulation of many important embryonic developmental programs involving repulsive and attractive guidance (e.g. axon pathfinding), adhesive fusion and assembly (e.g. neural tube closure and angiogenesis, respectively), and cell segregation across interfaces and along gradients of Eph and ephrin expression (e.g. skeletogenesis and cell positioning in the intestinal epithelium, respectively), Eph receptors also function in the adult. In the vertebrate brain, Eph receptors regulate synaptic plasticity via forward and/or reverse signaling, with expression of Eph receptor observed on either the pre- or post-synaptic membrane in different circuits. Other roles involve a tumor suppressor function in the prostate and undefined pathological functions in the progression of other cancers.

 

The Tables below contain accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

EphA Receptors

Family Members Eph A1 Eph A2 Eph A3 Eph A4 Eph A5
Other Names EPHT; EPHT1; Esk Eck; epithelial cell kinase; Myk2; Sek-2; Sek2 Chicken embryo kinase 4 (Cek4); ETK; ETK1; HEK4; human embryo kinase (HEK); Tyro4 Cek8; chicken embryo kinase 8; Hek8; human embryo kinase 8; MPK-3; Pag; Pagliaccio; Rtk1; Rtk2; Rtk4; Sek; Sek1; TYRO1; Zek1
Zek2
Brain specific kinase (bsk); chicken embryo kinase 7 (Cek7); human embyro 7 (Hek7); Rek1
Molecular Weight/
Structural Data
108 kDa; 976 aa 108.2 kDa; 976 aa 110 kDa; 983 aa 109.8 kDa; 986 aa 114.7 kDa; 1037 aa
Isoforms A1a
A1b
Not Known Truncated spliced variant Not Known Not Known
Species Human
Mouse
Human
Mouse
Human
Mouse
Rat
Chicken
Human
Mouse
Chicken
Human
Mouse
Rat
Chicken
Domain
Organization
Ephrin binding domain
2 fibronectin type-III domains
1 protein tyrosine kinase domain
1 SAM domain
Ephrin binding domain
2 fibronectin type-III domains
1 protein tyrosine kinase domain
1 SAM domain
Ephrin binding domain
2 fibronectin type-III domains
1 protein tyrosine kinase domain
1 SAM domain
Ephrin binding domain
2 fibronectin type-III domains
1 protein tyrosine kinase domain
1 SAM domain
Ephrin binding domain
2 fibronectin type-III domains
1 protein tyrosine kinase domain
1 SAM domain
Phosphorylation
Sites
Tyr599
Tyr605
Tyr781
Tyr930
Tyr588
Tyr594
Tyr772
Tyr921
Tyr596
Tyr602
Tyr779
Tyr596
Tyr602
Tyr779
Tyr928
Tyr650
Tyr656
Tyr833
Tyr982
Tissue
Distribution
Placenta
Overexpressed in several carcinomas
Epithelial Placenta
Widely expressed
Ubiquitous
Brain
Nervous system
Brain
Nervous system
Subcellular
Localization
Plasma membrane Plasma membrane Plasma membrane Plasma membrane Plasma membrane
Upstream
Activators
A-subclass ephrins A-subclass ephrins A-subclass ephrins A-subclass ephrins
Ephrin-B3
A-subclass ephrins
Binding Partners/
Downstream Activation
Pyk2
Ras
Rho
PI3K
Rac1
SLAP
Src
Fyn
Yes
Src
Fyn
Fes
Abl
PLCγ
RhoB
cdc42/Rac family of GTPases
Vav
ephexin
Not Known
Activators Not Known Not Known Not Known Not Known Not Known
Inhibitors Not Known Not Known Not Known Not Known Not Known
Selective
Activators
Not Known Not Known Not Known Not Known Not Known
Physiological
Function
Not Known Angiogenesis Retinocollicular topographic mapping; axon pathfinding Axon pathfinding; synaptic plasticity; neural crest migration; hindbrain segmentation; somitogenesis; neuroblast migration and proliferation; platelet aggregation Retinocollicular topographic mapping; vomero-nasal-accessory olfactory bulb topographic mapping; axon pathfinding; olfactory sensory neuronal topographic mapping; pathfinding
Disease
Relevance
Not Known Tumor neovascularization
Breast cancer
Glioblastomas
Lung cancer Sezary syndrome Glioblastomas

 

 

Family Members Eph A6 Eph A7 Eph A8 Eph A9 Eph A10
Other Names Ehk2; human embryo kinase 12 (Hek12)   Chicken embryo kinase 11 (cek11); Ebk; human embryo kinase 11(Hek11); MDK-1; mouse developmental kinase 1 (Mdk1) Eph and elk related tyrosine kinase (Eek); human embryo kinase 3 (HEK3) Not Known Not Known
Molecular Weight/
Structural Data
116.1 kDa; 1035 aa 112 kDa; 998 aa 111 kDa; 1005 aa 120-130 kDa; 969 aa 295
543 kDa
1008 aa
Isoforms Not Known Truncated splice variant Not Known Not Known EphA10s
EphA10*
EphA10
Species Mouse
Rat
Human
Mouse
Rat
Chicken
Human
Mouse
Rat
Chicken
Chicken Human
Domain
Organization
Ephrin binding domain
2 fibronectin type-III domains
1 protein tyrosine kinase domain
1 SAM domain
Ephrin binding domain
2 fibronectin type-III domains
1 protein tyrosine kinase domain
1 SAM domain
Ephrin binding domain
2 fibronectin type-III domains
1 protein tyrosine kinase domain
1 SAM domain
Ephrin binding domain
2 fibronectin type-III domains
1 protein tyrosine kinase domain
1 SAM domain
Ephrin binding domain
2 fibronectin type-III domains
1 protein tyrosine kinase domain
1 SAM domain
Phosphorylation
Sites
Tyr605
Tyr611
Tyr830
Tyr977
Tyr608
Tyr614
Tyr791
Tyr940
Tyr616
Tyr839
Not Known Not Known
Tissue
Distribution
Nervous system
Neurons
Ubiquitous Brain Kidney
Lung
Testis
Thymus
Testis
Subcellular
Localization
Plasma membrane Plasma membrane Plasma membrane Plasma membrane Plasma membrane
Upstream
Activators
A-subclass ephrins A-subclass ephrins A-subclass ephrins A-subclass ephrins A-subclass ephrins
Binding Partners/
Downstream Activation
Not Known Not Known Fyn
MAPK
LMW-PTP
PI3K
Not Known Not Known
Activators Not Known Not Known Not Known Not Known Not Known
Inhibitors Not Known Not Known Not Known Not Known Not Known
Selective
Activators
Not Known Not Known Not Known Not Known Not Known
Physiological
Function
Retinocollicular topographic mapping; vomero-nasal-accessory olfactory bulb topographic mapping; axon pathfinding Retinocollicular topographic mapping; vomero-nasal-accessory olfactory bulb topographic mapping; neural tube closure; axon pathfinding   Axon pathfinding Not Known Not Known
Disease
Relevance
Not Known Hepatocellular carcinomas Colon carcinomas Not Known Not Known

 

EphB Receptors

Family Members Eph B1 Eph B2 Eph B3 Eph B4 Eph B6
Other Names Chicken embryo kinase 6 (Cek6); Elk; EPHT2; human embryo kinase 6 (HEK6); NET Chicken embryo kinase 5 (Cek5); DRT; ELK-related protein kinase; EPHT3; ERK; ETECK; human embryo kinase 5 (HEK5); Nuk; Prkm5; Qek5; Sek3, Tyro5 Chicken embryo kinase 10 (Cek10); Etk2; HEK2; human embryo kinase 2; (HEK2); Mdk5; mouse developmental kinase 5; Sek4; Tyro6 Htk; mouse developmental kinase 2 (Mdk2) Myk1; Tyro11 HEP; Mep
Molecular Weight
109.9 kDa 117.5 kDa 110.3 kDa 108.2 kDa 109.2 kDa
Structural Data 984 aa 1055 aa 998 aa 987 aa 1006 aa
Isoforms Not Known Truncated splice variant Not Known Not Known Truncated splice variant
Species Human
Mouse
Rat
Chicken
Human
Mouse
Rat
Chicken
Human
Mouse
Rat
Chicken
Zebrafish
Xenopus
Human
Mouse
Human
Mouse
Domain
Organization
Ephrin binding domain
2 fibronectin type-III domains
1 protein tyrosine kinase domain
1 SAM domain
Ephrin binding domain
2 fibronectin type-III domains
1 protein tyrosine kinase domain
1 SAM domain
Ephrin binding domain
2 fibronectin type-III domains
1 protein tyrosine kinase domain
1 SAM domain
Ephrin binding domain
2 fibronectin type-III domains
1 protein tyrosine kinase domain
1 SAM domain
Ephrin binding domain
2 fibronectin type-III domains
1 protein tyrosine kinase domain
1 SAM domain
1 inactive/dead protein tyrosine kinase domain
Phosphorylation
Sites
Tyr594
Tyr600
Tyr778
Tyr928
Tyr596
Tyr602
Tyr605
Tyr611
Tyr780
Tyr930
Tyr608
Tyr614
Tyr792
Tyr942
Tyr590
Tyr596
Tyr774
Tyr924
Not Known
Tissue
Distribution
Brain
Kidney
Brain
Heart
Lung
Kidney
Placenta
Pancreas
Liver
Skeletal muscle
Nervous system
Ubiquitous Placenta
Fetal brain
Venous endothelial cells
Brain
Pancreas
Thymus
Subcellular
Localization
Plasma membrane Plasma membrane Plasma membrane Plasma membrane Plasma membrane
Upstream
Activators
B-subclass ephrins B-subclass ephrins
Ephrin A-5
B-subclass ephrins B-subclass ephrins B-subclass ephrins
Binding Partners/
Downstream Activation
Paxillin
NIK
Integrins
JNK
LMW-PTP
Nck
Grb2
Grb10
Synj1
Sdc2
Abl
Src
Yes
RasGAP
Nck
PLCγ
LMW-PTP
AF6
Pick-1
GRIP
Kalirin
Intersectin
NMDA receptor
RasGAP
Crk
AF6
RasGAP
Src
PI3K
AF6
Fyn
Rac/JNK
TCR/MAPK
Activators Not Known Not Known Not Known Not Known Not Known
Inhibitors Not Known Not Known Not Known Not Known Not Known
Selective
Activators
Hindbrain segmentation; skeletal development; axon pathfinding; angiogenesis; neural crest migration; dendritic spine development; neuroblast migration and proliferation; synaptic plasticity; platelet aggregation Hindbrain segmentation; skeletal development; axon pathfinding; retinocollicular topographic mapping; angiogenesis; midline fusion/septation; synaptic plasticity; neural crest migration; vestibular function; dendritic spine development; cell positioning in intestinal epithelium; neuroblast migration and proliferation; endocytosis Hindbrain segmentation; skeletal development; axon pathfinding; retinocollicular topographic mapping; angiogenesis; midline fusion/septation; neural crest migration; vestibular function; dendritic spine development; cell positioning in intestinal epithelium; neuroblast migration and proliferation; synaptic plasticity; endocytosis         Angiogenesis T cell regulation
Physiological
Function
Not Known Tumor suppressor in prostate and colon
Breast carcinomas
Hepatocellular domains
Colon carcinomas Tumor neovascularization
Breast carcinomas
Glioblastomas
Prostate cancer
Neuroblastomas
Metastatic melanoma
Disease
Relevance
         

 

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References